Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics.
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Pontillo
Joseph
J
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Wu
Dongpei
D
Ching
Brett
B
Hudson
Sarah
S
Genicot
Marc J
MJ
Gao
Yinghong
Y
Ewing
Todd
T
Fleck
Beth A
BA
Gogas
Kathleen
K
Aparicio
Anna
A
Wang
Hua
H
Wen
Jenny
J
Wade
Warren S
WS
D000069445:Atomoxetine Hydrochloride; D020650:Combinatorial Chemistry Techniques; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D011437:Propylamines / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007189:Indans; D014179:Neurotransmitter Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine